What is the recommended treatment for fungal meningitis?

Treatment of Fungal Meningitis

For cryptococcal meningitis, initiate induction therapy with amphotericin B deoxycholate (0.7-1.0 mg/kg/day) plus flucytosine (100 mg/kg/day) for 2 weeks, followed by fluconazole consolidation and maintenance therapy. 1

Cryptococcal Meningitis (Most Common Fungal Meningitis)

Induction Phase (First 2 Weeks)

The combination of amphotericin B plus flucytosine is superior to amphotericin B alone and represents the highest level of evidence (A-I) for HIV-infected patients. 1 This regimen has been shown in randomized controlled trials to increase survival and accelerate yeast clearance from cerebrospinal fluid. 2

• Standard regimen: Amphotericin B deoxycholate 0.7-1.0 mg/kg/day IV plus flucytosine 100 mg/kg/day orally for 2 weeks 1, 2
• For patients with renal impairment: Liposomal amphotericin B (3-4 mg/kg/day) or ABLC (5 mg/kg/day) plus flucytosine is preferred, particularly in transplant recipients who often have baseline renal dysfunction and concurrent nephrotoxic medications 1, 2
• When flucytosine is unavailable (common in resource-limited settings): Amphotericin B alone for 4-6 weeks or amphotericin B plus high-dose fluconazole (400-800 mg daily) for 2 weeks 1, 2, 3
• When amphotericin B cannot be used: Fluconazole 1200 mg daily plus flucytosine 100 mg/kg/day for 2 weeks, though this is less effective 1

Consolidation Phase (8 Weeks)

• Fluconazole 400 mg daily for 8 weeks after completing induction therapy 1, 2

Maintenance/Suppressive Phase

• Fluconazole 200 mg daily for at least 1 year to prevent relapse 1, 4
• In HIV-infected patients, maintenance therapy should continue until CD4 count >100 cells/mm³ with undetectable viral load for over 3 months 2
• For immunosuppressed patients (transplant recipients), 6-12 months of suppressive therapy is recommended 2

Critical Management of Intracranial Pressure

Elevated intracranial pressure is a major determinant of mortality and must be aggressively managed. 1, 2

• Measure opening pressure at baseline lumbar puncture 2
• If opening pressure >25 cm H₂O with symptoms: perform therapeutic lumbar punctures to reduce pressure by 50% or to ≤20 cm H₂O 2
• Repeat daily lumbar punctures until pressure stabilizes for 1-2 days 2
• Consider temporary percutaneous lumbar drains or ventriculostomy for patients requiring daily LPs 2
• Avoid acetazolamide and corticosteroids for ICP management (unless treating IRIS) 2
• Permanent ventriculoperitoneal shunts should only be placed after appropriate antifungal therapy has been initiated and conservative measures have failed 2

Monitoring Requirements

• Monitor flucytosine serum levels (target: 30-80 μg/mL or 40-60 mg/mL) and adjust dose based on renal function 2, 1
• Perform complete blood counts regularly due to bone marrow suppression risk with flucytosine 1
• Serial lumbar punctures to document CSF sterilization 1
• Monitor serum electrolytes, renal function for amphotericin B nephrotoxicity 2
• Treatment duration for initial therapy is 10-12 weeks after CSF becomes culture-negative 4, 2

Special Populations

HIV-infected patients: Delay antiretroviral therapy initiation for 2-10 weeks after starting antifungal treatment to reduce risk of immune reconstitution inflammatory syndrome (IRIS) 1

Pediatric patients: Amphotericin B 0.7-1.0 mg/kg/day plus flucytosine for induction, followed by fluconazole 12 mg/kg on first day, then 6 mg/kg daily 1, 4

Immunocompetent patients: Follow similar induction-consolidation strategy, but may not require prolonged maintenance therapy if immunosuppression can be reduced 2

Histoplasma Meningitis

Histoplasma meningitis requires aggressive treatment due to poor outcomes, with 20-40% mortality despite therapy. 2

• Induction: Amphotericin B 0.7-1.0 mg/kg/day to complete 35 mg/kg total dose over 3-4 months 2
• Consolidation/maintenance: Fluconazole 800 mg daily for 9-12 months after completing amphotericin B to reduce relapse risk 2
• Itraconazole is discouraged for meningitis despite better activity against Histoplasma because it does not penetrate CSF 2
• Chronic fluconazole maintenance therapy (800 mg daily) should be considered for patients who relapse despite full courses 2

Candida Meningitis

Candida meningitis is rare but has poor prognosis and requires combination therapy. 2

• Preferred regimen: Liposomal amphotericin B plus flucytosine for at least 2 weeks, with treatment duration ranging from 4-10 weeks depending on response 2
• Amphotericin B deoxycholate plus flucytosine has been used successfully in HIV-infected patients, with 4 of 5 patients responding 2
• High-dose fluconazole (400-800 mg daily) has been used as follow-up or long-term suppressive therapy 2
• Treatment should continue for minimum 4 weeks after resolution of all signs and symptoms 2
• Remove prosthetic devices (ventricular shunts, etc.) associated with neurosurgical procedures 2

Common Pitfalls to Avoid

• Failure to test for HIV in all patients presenting with cryptococcal meningitis 1
• Inadequate management of elevated intracranial pressure, which is a leading cause of death 1, 2
• Premature initiation of antiretroviral therapy in HIV patients—wait 2-10 weeks to avoid IRIS 1
• Relying solely on cryptococcal antigen titers to guide treatment decisions rather than clinical and CSF parameters 2, 1
• Failure to monitor for drug toxicities, especially amphotericin B nephrotoxicity and flucytosine bone marrow suppression 1, 2
• Using fluconazole monotherapy for induction in cryptococcal meningitis, which is associated with significantly increased mortality compared to combination therapy 3
• Inadequate treatment duration—stopping therapy before CSF sterilization and clinical resolution leads to high relapse rates 2